Metered dose inhalers (MDIs) have long been used to deliver medicaments, such as bronchodilator drugs and steroids, to the areas of patients needing treatment. Compared with oral administration of bronchodilators, inhalation therapy using MDIs frequently has the advantage of relatively rapid onset of action and relatively low instance of systemic side effects.
In general, MDIs are dependent upon the propulsive force of a propellant to help transport the medicament to the area or areas needing treatment, which sometimes are referred to herein as the “target area.” The propellant has heretofore generally comprised a mixture of liquefied chlorofluorocarbons (CFC's) selected to have the vapor pressure necessary to produce the desired propulsive force while at the same time providing stability of the medicament formulation. Methane and ethane series CFCs, such tetrachloromethane (CFC-11), trichlorofluoromethane (CFC-12) and 1,2 dichlorotetrafluoroethane (CFC-114), have commonly been used as propellants in aerosol formulations for inhalation administration.
The use of CFCs has environmental drawbacks. It is now known that CFC's tend to react with the ozone layer around the earth and thereby result in some level of ozone depletion. As a result various governmental and international organizations have been engaged in efforts to reduce or eliminate the use of CFCs. The volume of CFCs which have been used in connection with MDIs may be considered low compared to other uses, such as refrigerants and blowing agents. Nevertheless, a potential ozone depletion advantage may be achieved by reducing or eliminating CFCs from MDIs and other medicament delivery systems.
Because of the potential damage to the earth's ozone layer caused by chlorine-containing compounds (such as chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) and the like), there has thus been an increasing need for new fluorocarbon and hydrofluorocarbon compounds and compositions that offer alternatives with reduced ozone depletion potential. For example, efforts are under way to replace chlorine-containing propellants with non-chlorine-containing compounds that will not deplete the ozone layer, such as hydrofluorocarbons (HFCs).
U.S. Pat. No. 5,776,434—Purewal, et al. has recognized the ozone depletion problem of CFCs and has proposed the use of a non-chlorine containing compound, namely, 1,1,1,2-tetrafluoroethane (sometimes referred to herein as HFA-134a or HFC-134a) as a propellant for medicinal aerosol formulations when used in combination with a surface active agent and an adjuvant having a higher polarity than 1,1,1,2-tetrafluoroethane. However, in 1998 the International Programme on Chemical Safety (IPCS), published a Concise International Chemical Assessment Document (No. 11) indicating that 1,1,1,2-tetrafluorethane has a significant global warming potential.
HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane) has also been proposed as low ozone depletion potential substitute for CFCs in MDIs. However, this compound also has a significant global warming potential.
U.S. Pat. No. 6,111,150 describes chlorofluor- and fluoro-substituted propenes as being “useful as an intermediate of medicines . . . ” (col.2, I. 4). However, there is no disclosure or suggestion of MDIs or any of the propellant materials used in MDIs. U.S. Pat. Nos. 3,723,318 and 3,884,826 each describes the use of trifluoropropene in connection with aerosol propellants and refrigerants, but there is no disclosure or suggestion in these patents relating to MDIs, nor is there any disclosure or suggestion regarding the use of tetrafluoropropene as an aerosol or in connection with MDIs.
Bromine-containing halocarbon additives have been suggested for use in connection with efforts to reduce the flammability of numerous materials, including aerosol propellants, in U.S. Pat. No. 5,900,185—Tapscott. The additives described in this patent are said to be characterized by high efficiency and short atmospheric lifetimes, that is, low ozone depletion potential (ODP) and a low global warming potential (GWP). The patent discloses the use of such compounds in amounts of from about 0.1 to about 20 percent by weight.
While the brominated olefins described in Topscott may have some level of effectiveness in connection with use as anti-flammability agents in connection with certain materials, there is no disclosure of the use of such materials as an aerosol or propellant. Furthermore, it is believed that such compounds may also have certain disadvantages. For example, applicants have come to recognize that many of the compounds identified in Topscott will have a relatively low efficiency as a blowing agent due to the relatively high molecular weight of such compounds. In addition, it is believed that many of the compounds disclosed in Tapscott will encounter problems when used as a blowing agent due to the relatively high boiling point of such compounds. Moreover, it is understood by applicants that many compounds which have a high level of no means substitution may possess undesirable toxicity properties and/or other undesirable properties, such as potentially environmentally undesirable bioaccumulation.
Thus, applicants have recognized a need for compounds, compositions, systems, devices and methods for medicament delivery that at once provide relatively low ozone depletion potential and relatively low global warming potential. Moreover, applicants have recognized that any composition, including any propellant contained therein, must also possess properties which ensure the efficacy of the medicament, such as medicament stability, low- or no-toxicity, and compatibility with the other components of the medicament delivery system.